Abstract
Purpose
Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies.
Methods
In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5–12, and had their end-of-study visit between days 14 and 16.
Results
Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration–time curve from time 0 to infinity (AUCinf) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUCinf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment–emergent adverse events were gastrointestinal and mild.
Conclusion
Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.
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Funding
The clinical trial reported in this manuscript was sponsored by Sanofi. Medical writing support was provided by Shawn Vahabzadeh, PharmD, of MediTech Media, Ltd, and funded by Bristol Myers Squibb.
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KO, MP, and GK are employees of and hold equity ownership in Bristol Myers Squibb. WBS declares no conflict of interest. CX are employed by and hold equity ownership in Sanofi and JY is an employee of Sanofi.
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All study procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments.
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Ogasawara, K., Smith, W.B., Xu, C. et al. Pharmacokinetics and tolerability of fedratinib, an oral, selective Janus kinase 2 inhibitor, in subjects with renal or hepatic impairment. Cancer Chemother Pharmacol 85, 1109–1117 (2020). https://doi.org/10.1007/s00280-020-04084-2
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DOI: https://doi.org/10.1007/s00280-020-04084-2